A novel systematic investigation of exposure to a range of viruses found at least 22 viral illnesses were linked with an increased risk of future neurodegenerative disease; for some exposures the risk persisted up to 15 years after infection.
The results, published in the journal Neuron, are particularly concerning given growing evidence of and concern regarding concomitant neurologic symptoms associated with SARS-CoV-2 infection and with postacute sequelae of COVID-19. or long COVID.
The study authors, from the Center for Alzheimer’s and Related Dementias (CARD), National Institute on Aging of the National Institutes of Health, found the viral infection that was associated with the greatest number of NDDs was influenza with pneumonia; the NDD associated with the most viral infections was generalized dementia. The investigators stress that there are vaccines available against many of the implicated viruses.
Prompted by recent data connecting the Epstein Barr virus to increased risk of multiple sclerosis (MS) and earlier studies that suggest an association between herpes simplex and Alzheimer disease (AD), Mike Nalls, PhD, of CARD, and coauthors took advantage of 2 vast data repositories to investigate the potential for other viral illnesses to pose similar risks.
The team first sourced time series data from the FinnGen project, a Finnish biobank with genotyping data for more than 300 000 individuals, for individuals diagnosed with 1 of 6 neurodegenerative conditions: Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), generalized dementia, vascular dementia, Parkinson disease, and MS. They followed this with a search for those who had a history of hospitalization for a viral illness. To confirm these findings, they sought replication data from the UK Biobank, host to genotyping data from approximately 500 000 UK residents.
Nalls and colleagues found 45 signficant associations in the longitudinal data from FinnGen between exposure to a viral infection and subsequent risk of developing a NDD; 22 of these associations were replicated in the cross-sectional data from participants aged ≥60 years obtained from the UKB.
They found that dementia was the NDD associated with the greatest number of virus exposures, linked to 6: influenza, influenza with pneumonia, viral pneumonia, viral encephalitis, viral warts, and other viral diseases.
The largest effect association observed was between viral encephalitis and AD. Investigators found 24 of the 406 (5.9%) cases of viral encephalitis went on to develop AD, higher than the general prevalence of AD (<3%) among individuals in the FinnGen control population.
Influenza (with or without pneumonia) was the most commonly associated viral endpoint, associated with all the neurodegenerative diseases studied except MS.
Viral encephalitis, intestinal infections, and varicella-zoster virus all were significant and replicated for more than a single NDD.
The researchers note that none of the viruses studied was associated with a protective effect.
In general, the greatest risk of being diagnosed with a NDD was within the first year of infection, found true for 16 associations. Six of the associations were significant if the infection had occurred 5 to 15 years before diagnosis. The 2 pairs with the most long-lasting bidirectional effects were AD and influenza and dementia and Bell palsy.
Nalls et al point out that the pairings with the strongest effect, eg, AD and viral encephalitis, are rare. However, many of the common pairings found—such as generalized dementia and influenza—come with moderately increased risk.
“Strikingly, vaccines are currently available for some of these viruses, including influenza, shingles (varicella-zoster), and pneumonia,” the authors wrote. Vaccination will not prevent all infection, but vaccines are known to reduce hospitalization rates significantly. “This evidence suggests that vaccination may mitigate some risk of developing NDD,” they added.
The researchers cite evidence for reduced risk of AD and PD associated with vaccination against influenza, pneumonia, and varicella zoster. And yet, “influenza vaccination coverage in the United States is typically less than 50%." Further, just one-third (35%) of people aged ≥60 years have received a shingles vaccine, they wrote.
“Neurodegenerative disorders are a collection of diseases for which there are very few effective treatments and many risk factors,” said co-author Andrew B. Singleton, PhD, CARD director and NIH Distinguished Investigator, in an NIH statement. “Our results support the idea that viral infections and related inflammation in the nervous system may be common — and possibly avoidable — risk factors for these types of disorders.”
“The results of this study provides researchers with several new critical pieces of the neurodegenerative disorder puzzle,” added Nalls. “In the future, we plan to use the latest data science tools to not only find more pieces but also help researchers understand how those pieces, including genes and other risk factors, fit together.”
Reference: Levine KS, Leonard HL, Blauwendraat C, et al. Virus exposure and neurodegenerative disease risk across national biobanks. Neuron. Published online January 11, 2023. doi:10.1016/j.neuron.2022.12.029